Rate-reducing membrane for release of an agent

ABSTRACT

A membrane that reduces the rate at which a therapeutic substance is released from an implantable medical device, such as a stent, is disclosed.

CROSS REFERENCE

This is a continuation of application Ser. No. 11/330,926, filed on Jan.11, 2006, which is a continuation of Ser. No. 10/760,132 filed on Jan.15, 2004, which is a continuation of application Ser. No. 09/966,787filed on Sep. 27, 2001 (U.S. Pat. No. 6,753,071).

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to a coating disposed on an implantable device,one example of which is a stent, for reducing the release rate of anagent carried by the device.

2. Description of the Background

Percutaneous transluminal coronary angioplasty (PTCA) is a procedure fortreating heart disease. A catheter assembly having a balloon portion isintroduced percutaneously into the cardiovascular system of a patientvia the brachial or femoral artery. The catheter assembly is advancedthrough the coronary vasculature until the balloon portion is positionedacross the occlusive lesion. Once in position across the lesion, theballoon is inflated to a predetermined size to remodel the vessel wall.The balloon is then deflated to a smaller profile to allow the catheterto be withdrawn from the patient's vasculature.

A problem associated with the above procedure includes formation ofintimal flaps or torn arterial linings, which can collapse and occludethe conduit after the balloon is deflated. Vasospasms and recoil of thevessel wall also threaten vessel closure. Moreover, thrombosis andrestenosis of the artery may develop over several months after theprocedure, which may necessitate another angioplasty procedure or asurgical by-pass operation. To reduce the partial or total occlusion ofthe artery by the collapse of arterial lining and to reduce the chanceof the development of thrombosis and restenosis, an expandable,intraluminal prosthesis, one example of which is a stent, is implantedin the lumen to maintain the vascular patency.

Stents act as scaffoldings, functioning to physically hold open and, ifdesired, to expand the wall of the passageway. Typically, stents arecapable of being compressed so that they can be inserted through smalllumens via catheters and then expanded to a larger diameter once theyare at the desired location. Examples in the patent literaturedisclosing stents that have been applied in PTCA procedures include U.S.Pat. No. 4,733,665 issued to Palmaz, U.S. Pat. No. 4,800,882 issued toGianturco, and U.S. Pat. No. 4,886,062 issued to Wiktor. Mechanicalintervention via stents has reduced the rate of restenosis as comparedto balloon angioplasty. Yet, restenosis is still a significant clinicalproblem with rates ranging from 20-40%. When restenosis does occur inthe stehted segment, its treatment can be challenging, as clinicaloptions are more limited as compared to lesions that were treated solelywith a balloon.

Stents are used not only for mechanical intervention but also asvehicles for providing biological therapy. Biological therapy can beachieved by medicating the stents. Medicated stents provide for thelocal administration of a therapeutic substance at the diseased site. Inorder to provide an efficacious concentration to the treated site,systemic administration of such medication often produces adverse oreven toxic side effects for the patient. Local delivery is a preferredmethod of treatment in that smaller total levels of medication areadministered in comparison to systemic dosages, but are concentrated ata specific site. Local delivery thus produces fewer side effects andachieves more favorable results.

One proposed method for medicating stents included use of aheparin-coated metallic stent, whereby a heparin coating was tonicallyor covalently bonded to the stent. Significant disadvantages associatedwith the aforementioned method include loss of the therapeutic substancefrom the body of the stent during delivery and expansion of the stent aswell as lack of control of the release rate of the substance from thestent.

Another proposed method of medicating stents involved the use of apolymeric carrier coated onto the surface of the stent. A compositionincluding a solvent, a polymer dissolved in the solvent, and atherapeutic substance dispersed in the blend is applied to the stent byimmersing the stent in the composition or by spraying the compositiononto the stent. The solvent is allowed to evaporate, leaving on thestent strut surfaces a coating of the polymer and the therapeuticsubstance impregnated in the polymer.

Depending on the physiological mechanism targeted, the therapeuticsubstance may be required to be released at an efficacious concentrationfor an extended duration of time. Increasing the quantity of thetherapeutic substance in the polymeric coating can lead to poor coatingmechanical properties, inadequate coating adhesion, and overly rapidrate of release. Increasing the quantity of the polymeric compound byproducing a thicker coating can perturb the geometrical and mechanicalfunctionality of the stent as well as limit the procedures for which thestent can be used.

It is desirable to increase the residence time of a substance at thesite of implantation, at a therapeutically useful concentration, withoutneeding to add a greater percentage of the therapeutic substance to thepolymeric coating and without needing to apply a significantly thickercoating.

SUMMARY OF THE INVENTION

In accordance with one embodiment of the present invention, a method offorming a coating for a medical device, such as a stent, carrying anagent is provided. The method includes applying a first compositionincluding a polymer to at least a portion of a medical device to form afirst polymeric coating. The polymer has a solubility parameter notgreater than approximately 11.5 (cal/cm³)^(1/2). The first polymericcoating reduces the rate of release of the agent from the medicaldevice. In some embodiments of the method, the polymer of the firstcoating additionally has an equilibrium water absorption factor of lessthan about 5% by weight under physiologic conditions.

Also provided is a composition for forming a coating on a medicaldevice. The composition includes a solvent and a hydrophobic polymerdissolved in the solvent. The hydrophobic polymer has an equilibriumwater absorption factor of less than about 5% by weight underphysiological conditions. In some embodiments, the hydrophobic polymeradditionally has a solubility parameter not greater than approximately11.5 (cal/cm³)^(1/2).

An implantable medical device for carrying a therapeutic agent is alsoprovided. The device includes a first coating including a polymericmaterial. The polymeric material has a solubility parameter not greaterthan approximately 11.5 (cal/cm³)^(1/2). The first coating reduces therate of release of the agent. In some embodiments, the polymericmaterial additionally has an equilibrium water absorption factor of lessthan about 5% by weight under physiologic conditions.

Polymeric material suitable for use in the first coating of the presentinvention include hydrophobic and non-polar polymers such as, but notlimited to, polytetrafluoroethylene, perfluoro elastomers, amorphousfluoropolymer, ethylene-tetrafluoroethylene copolymer,fluoroethylene-alkyl vinyl ether copolymer, polyhexafluoropropylene, lowdensity linear polyethylenes having high molecular weights,ethylene-olefin copolymers, atactic polypropylene, polyisobutene,polybutylenes, styrene-ethylene-styrene block copolymers,styrene-butylene-styrene block copolymers,styrene-ethylene/butylene-styrene block copolymers,styrene-butadiene-styrene block copolymers, ethylene-anhydridecopolymers, ethylene vinyl acetate copolymers, ethylene-acrylic acidcopolymers, ethylene methacrylic acid copolymers, polyurethanes with apolydimethylsiloxane soft segment, and cross-linked silicone elastomers.

The medical device can be, for example, a balloon-expandable stent, aself-expandable stent, a graft, a stent graft. The medical device caninclude cavities containing an active ingredient for the release of theactive ingredient when the device is implanted. Alternatively, thedevice can include a reservoir coating carrying an active ingredient.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1A illustrates a fluid on a solid substrate having a contact angleΦ₁;

FIG. 1B illustrates a fluid on a solid substrate having a contact angleΦ₂;

FIG. 2A illustrates a first coating deposited over an implantablemedical substrate in accordance with one embodiment of the presentinvention;

FIG. 2B illustrates a first coating deposited over an implantablemedical substrate in accordance with another embodiment of the presentinvention; and

FIG. 2C illustrates a pair of coatings deposited over an implantablemedical substrate in accordance with yet another embodiment of thepresent invention.

DETAILED DESCRIPTION OF THE EMBODIMENTS Composition for Forming anOptional Primer Layer

The presence of an active ingredient in a polymeric matrix can interferewith the ability of the matrix to adhere effectively to the surface ofthe device. Increasing the quantity of the active ingredient reduces theeffectiveness of the adhesion. High drug loadings of, for example,10-40% by weight in the coating can hinder the retention of the coatingon the surface of the device. A primer layer can serve as a functionallyuseful intermediary layer between the surface of the device and anactive ingredient-containing or reservoir coating. The primer layerprovides an adhesive tie between the reservoir coating and thedevice—which, in effect, would also allow for the quantity of the activeingredient in the reservoir coating to be increased without compromisingthe ability of the reservoir coating to be effectively contained on thedevice during delivery and, if applicable, expansion of the device.

The embodiments of the composition for an optional primer layer areprepared by conventional methods wherein all components are combined,then blended. More particularly, in accordance with one embodiment, apredetermined amount of a polymer or a prepolymer is added to apredetermined amount of a solvent or a combination of solvents. Themixture can be prepared at ambient pressure and under anhydrousatmosphere. Heating and stirring and/or mixing can be employed to effectdissolution of the polymer into the solvent.

“Polymer,” “poly,” and “polymeric” are defined as compounds that are theproduct of a polymerization reaction and are inclusive of homopolymers,copolymers, terpolymers etc., including random, alternating, block, andgraft variations thereof. The polymers should have a high capacity ofadherence to the surface of an implantable device, such as a metallicsurface of a stent.

Representative examples of suitable polymeric materials include, but arenot limited to, polyisocyanates, such as triisocyanurate andpolyisocyanate polyether polyurethanes based on diphenylmethanediisocyanate; acrylates, such as copolymers of ethyl acrylate andmethacrylic acid; titanates, such as tetra-iso-propyl titanate andtetra-n-butyl titanate; zirconates, such as n-propyl zirconate andn-butyl zirconate; silane coupling agents, such as3-aminopropyltriethoxysilane and (3-glydidoxypropyl)methyldimethoxysilane; high amine content polymers, such aspolyethyleneamine, polyallylamine, and polylysine; polymers with a highcontent of hydrogen bonding groups, such as polyethylene-co-polyvinylalcohol, ethylene vinyl acetate, and melamine formaldehydes; andunsaturated polymers and prepolymers, such as polycaprolactonediacrylates, polyacrylates with at least two acrylate groups, andpolyacrylated polyurethanes. With the use of unsaturated prepolymers, afree radical or UV initiator can be added to the composition for thethermal or UV curing or cross-linking process, as is understood by oneof ordinary skill in the art.

Biocompatible polymers can also be used for the primer material. Thepolymer can be bioabsorbable or biostable. Bioabsorbable polymers thatcould be used include poly(hydroxyvalerate), poly(L-lactic acid),polycaprolactone, poly(lactide-co-glycolide), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester,polyanhydride, poly(glycolic acid), poly(D,L-lactic acid), poly(glycolicacid-co-trimethylene carbonate), polyphosphoester, polyphosphoesterurethane, poly(amino acids), cyanoacrylates, poly(trimethylenecarbonate), poly(iminocarbonate), copoly(ether-esters) (e.g. PEO/PLA),polyalkylene oxalates, polyphosphazenes and biomolecules such as fibrin,fibrinogen, cellulose, starch, collagen and hyaluronic acid. Inaddition, biostable polymers such as polyurethanes, silicones, andpolyesters could be used. Other polymers could also be used if they canbe dissolved and cured or polymerized on the stent such as polyolefins,polyisobutylene and ethylene-alphaolefin copolymers; acrylic polymersand copolymers; vinyl halide polymers and copolymers, such as polyvinylchloride; polyvinyl ethers, such as polyvinyl methyl ether;polyvinylidene halides, such as polyvinylidene fluoride andpolyvinylidene chloride; polyacrylonitrile, polyvinyl ketones; polyvinylaromatics, such as polystyrene; polyvinyl esters, such as polyvinylacetate; copolymers of vinyl monomers with each other and olefins, suchas ethylene-methyl methacrylate copolymers, acrylonitrile-styrenecopolymers, ABS resins, and ethylene-vinyl acetate copolymers;polyamides, such as Nylon 66 and polycaprolactam; alkyd resins;polycarbonates; polyoxymethylenes; polyimides; polyethers; epoxy resins;polyurethanes; rayon, rayon-triacetate; cellulose, cellulose acetate,cellulose butyrate; cellulose acetate butyrate; cellophane; cellulosenitrate; cellulose propionate; cellulose ethers; and carboxymethylcellulose.

Ethylene vinyl alcohol is a very suitable choice of polymer for theprimer layer. The copolymer possesses good adhesive qualities to thesurface of a stent, particularly stainless steel surfaces, and hasillustrated the ability to expand with a stent without any significantdetachment of the copolymer from the surface of the stent. Ethylenevinyl alcohol copolymer, commonly known by the generic name EVOH or bythe trade name EVAL, refers to copolymers comprising residues of bothethylene and vinyl alcohol monomers. One of ordinary skill in the artunderstands that ethylene vinyl alcohol copolymer may also be aterpolymer so as to include small amounts of additional monomers, forexample less than about five (5) mole percentage of styrenes, propylene,or other suitable monomers. In a useful embodiment, the copolymercomprises a mole percent of ethylene of from about 27% to about 48%.Ethylene vinyl-alcohol copolymers are available commercially fromcompanies such as Aldrich Chemical Company, Milwaukee, Wis., or EVALCompany of America, Lisle, Ill., or can be prepared by conventionalpolymerization procedures that are well known to one of ordinary skillin the art.

The solvent should be compatible with the polymer and should be capableof placing the polymer into solution at the concentration desired.Particularly useful solvents should also be able to expand the chains ofthe polymer for maximum interaction with the surface of the device, suchas a metallic surface of a stent. Examples of suitable solvents include,but are not limited to, dimethylsulfoxide (DMSO), chloroform, acetone,water (buffered saline), xylene, acetone, methanol, ethanol, 1-propanol,tetrahydrofuran, 1-butanone, dimethylformamide, dimethylacetamide,cyclohexanone, ethyl acetate, methylethylketone, propylene glycolmonomethylether, isopropanol, N-methyl pyrrolidinone, toluene andmixtures thereof.

By way of example, and not limitation, the polymer can comprise fromabout 0.1% to about 35%, more narrowly from about 2% to about 20% byweight of the total weight of the composition, and the solvent cancomprise from about 65% to about 99.9%, more narrowly from about 80% toabout 98% by weight of the total weight of the composition. A specificweight ratio is dependent on factors such as the material from which theimplantable device is made, the geometrical structure of the device, thechoice of polymer-solvent combination, and the method of application.

In accordance with another embodiment, a fluid can be added to thecomposition to enhance the wetting of the primer composition for a moreuniform coating application. To enhance the wetting of the composition,a suitable fluid typically has a high capillary permeation. Capillarypermeation or wetting is the movement of a fluid on a solid substratedriven by interfacial energetics. Capillary permeation is quantitated bya contact angle, defined as an angle at the tangent of a droplet in afluid phase that has taken an equilibrium shape on a solid surface. Alow contact angle indicates a higher wetting liquid. A suitably highcapillary permeation corresponds to a contact angle less than about 90°.FIG. 1A illustrates a fluid droplet 10A on a solid substrate 12, forexample a stainless steel surface. Fluid droplet 10A has a highcapillary permeation that corresponds to a contact angle Φ₁, which isless than about 90°. In contrast, FIG. 1B illustrates a fluid droplet10B on solid substrate 12, having a low capillary permeation thatcorresponds to a contact angle Φ₂, which is greater than about 90°. Thewetting fluid, typically, should have a viscosity not greater than about50 centipoise, narrowly about 0.3 to about 5 centipoise, more narrowlyabout 0.4 to about 2.5 centipoise. The wetting fluid, accordingly, whenadded to the composition, reduces the viscosity of composition.

The wetting fluid should be compatible with the polymer and the solventand should not precipitate the polymer. The wetting fluid can also actas the solvent. Useful examples of the wetting fluid include, but arenot limited to, tetrahydrofuran (THF), dimethylformamide (DMF),1-butanol, n-butyl acetate, dimethyl acetamide (DMAC), and mixtures andcombinations thereof. By way of example and not limitation, the polymercan comprise from about 0.1% to about 35%, more narrowly from about 2%to about 20% by weight of the total weight of the composition; thesolvent can comprise from about 19.9% to about 98.9%, more narrowly fromabout 58% to about 84% by weight of the total weight of the composition;and the wetting fluid can comprise from about 1% to about 80%, morenarrowly from about 5% to about 40% by weight of the total weight of thecomposition. The specific weight ratio of the wetting fluid depends onthe type of polymer, solvent and wetting fluid employed as wells as theweight ratio of the polymer and the solvent.

Composition for Forming an Active Ingredient-Containing Coating

The embodiments of the composition for an active ingredient-containingor reservoir coating are prepared by conventional methods wherein allcomponents are combined, then blended. More particularly, in accordancewith one embodiment, a predetermined amount of a polymeric compound isadded to a predetermined amount of a compatible solvent. The polymericcompound can be added to the solvent at ambient pressure and underanhydrous atmosphere. If necessary, gentle heating and stirring and/ormixing can be employed to effect dissolution of the polymer into thesolvent, for example 12 hours in a water bath at about 60° C.

Sufficient amounts of an active ingredient are dispersed in the blendedcomposition of the polymer and the solvent. The polymer can comprisefrom about 0.1% to about 35%, more narrowly from about 2% to about 20%by weight of the total weight of the composition, the solvent cancomprise from about 59.9% to about 99.8%, more narrowly from about 79%to about 89% by weight of the total weight of the composition, and theactive ingredient can comprise from about 0.1% to about 40%, morenarrowly from about 1% to about 9% by weight of the total weight of thecomposition. More than 9% by weight of the active ingredient couldadversely affect characteristics that are desirable in the polymericcoating, such as adhesion of the coating to the device. With the use ofthe optional primer layer, weight ratios of more than 9% for the activeingredient are achievable without compromising the effectiveness of theadhesion. Selection of a specific weight ratio of the polymer andsolvent is dependent on factors such as, but not limited to, thematerial from which the device is made, the geometrical structure of thedevice, and the type and amount of the active ingredient employed.

Optionally, a second solvent, such as tetrahydrofuran (THF) ordimethylformamide (DMF), can be used to improve the solubility of anactive ingredient in the composition. The second solvent can be added tothe composition or the active ingredient can be added to the secondsolvent prior to admixture with the blend. In this embodiment, thepolymer can comprise from about 0.1% to about 35%, more narrowly fromabout 2% to about 20% by weight of the total weight of the composition,the solvent can comprise from about 19.8% to about 98.8%, more narrowlyfrom about 49% to about 79% by weight of the total weight of thecomposition; the second solvent can comprise from about 1% to about 80%,more narrowly from about 5% to about 40% by weight of the total weightof the composition; and the active ingredient can comprise from about0.1% to about 40%, more narrowly from about 1% to about 9% by weight ofthe total weight of the composition. Selection of a specific weightratio of the polymer, the solvent, and the second solvent is dependenton factors such as, but not limited to, the material from which theimplantable device is made, the geometrical structure of the device, andthe type and amount of the active ingredient employed. The particularweight percentage of the active ingredient mixed within the compositiondepends on factors such as duration of the release, cumulative amount ofrelease, and release rate that is desired.

The active ingredient should be in true solution or saturated in theblended composition. If the active ingredient is not completely solublein the composition, operations including mixing, stirring, and/oragitation can be employed to effect homogeneity of the residues. Theactive ingredient can also be first added to the second solvent prior toadmixing with the composition. The active ingredient may be added sothat the dispersion is in fine particles. The mixing of the activeingredient can be conducted in an anhydrous atmosphere, at ambientpressure, and at room temperature such that supersaturating the activeingredient is not achieved.

The active ingredient may be any substance capable of exerting atherapeutic or prophylactic effect in the practice of the presentinvention. Examples of such active ingredients includeantiproliferative, antineoplastic, antiinflammatory, antiplatelet,anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic, andantioxidant substances as well as combinations thereof. A suitableexample of an antiproliferative substance is actinomycin D, orderivatives and analogs thereof (manufactured by Sigma-Aldrich 1001 WestSaint Paul Avenue, Milwaukee, Wis. 53233; or COSMEGEN available fromMerck). Synonyms of actinomycin D include dactinomycin, actinomycin IV,actinomycin I₁, actinomycin X₁, and actinomycin C₁. Examples of suitableantineoplastics include paclitaxel and docetaxel. Examples of suitableantiplatelets, anticoagulants, antifibrins, and antithrombins includesodium heparin, low molecular weight heparin, hirudin, argatroban,forskolin, vapiprost, prostacyclin and prostacyclin analogs, dextran,D-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole,glycoprotein IIb/IIIa platelet membrane receptor antagonist, recombinanthirudin, thrombin inhibitor (available from Biogen), and 7E-3B® (anantiplatelet drug from Centocore). Examples of suitable antimitoticagents include methotrexate, azathioprine, vincristine, vinblastine,fluorouracil, adriamycin, and mutamycin. Examples of suitable cytostaticor antiproliferative agents include angiopeptin (a somatostatin analogfrom Ibsen), angiotensin converting enzyme inhibitors such as CAPTOPRIL(available from Squibb), CILAZAPRIL (available from Hoffman-LaRoche), orLISINOPRIL (available from Merck); calcium channel blockers (such asNifedipine), colchicine, fibroblast growth factor (FGF) antagonists,histamine antagonist, LOVASTATIN (an inhibitor of HMG-CoA reductase, acholesterol lowering drug from Merck), monoclonal antibodies (such asPDGF receptors), nitroprusside, phosphodiesterase inhibitors,prostaglandin inhibitor (available form Glazo), Seramin (a PDGFantagonist), serotonin blockers, thioprotease inhibitors,triazolopyrimidine (a PDGF antagonist), and nitric oxide. Othertherapeutic substances or agents that may be appropriate includealpha-interferon; genetically engineered epithelial cells;dexamethasone; rapamycin; estradiol; clobetasol propionate; cisplatin;and carboplatin. Exposure of the composition to the active ingredientshould not adversely alter the active ingredient's composition orcharacteristic. Accordingly, the particular active ingredient isselected for compatibility with the blended composition.

The dosage or concentration of the active ingredient required to producea therapeutic effect should be less than the level at which the activeingredient produces toxic effects and greater than the level at whichnon-therapeutic results are obtained. The dosage or concentration of theactive ingredient required to inhibit the desired cellular activity ofthe vascular region, for example, can depend upon factors such as theparticular circumstances of the patient; the nature of the trauma; thenature of the therapy desired; the time over which the ingredientadministered resides at the vascular site; and if other bioactivesubstances are employed, the nature and type of the substance orcombination of substances. Therapeutically effective dosages can bedetermined empirically, for example by infusing vessels from suitableanimal model systems and using immunohistochemical, fluorescent orelectron microscopy methods to detect the agent and its effects, or byconducting suitable in vitro studies. Standard pharmacological testprocedures to determine dosages are understood by one of ordinary skillin the art.

The polymer chosen should be biocompatible so as not to cause anyadverse response. The solvent chosen should be capable of placing thepolymer into solution at the concentration desired. Representativeexamples of biocompatible polymers as well as of suitable solventsinclude those provided above with reference to the primer composition.With the use of a low ethylene content, e.g., 29 mol %, ethylene vinylalcohol, for example, a suitable solvent is iso-propylalcohol (IPA)admixed with water e.g., from about 40% to about 60% by weight IPA. Ifan optional primer layer is used, the choice of polymer for thereservoir coating can be the same as that selected for the primer so asto eliminate any interfacial incompatibilities.

Composition for Forming the Rate-Reducing Membrane

If it is desired to increase the rate at which an active ingredientdiffuses through a membrane, the membrane should be made of a polymer inwhich the active ingredient readily dissolves. By contrast, if it isdesired to decrease the rate at which an active ingredient diffusesthrough a membrane, the membrane should be made of a polymer in whichthe active ingredient is less soluble. The purpose of the rate-reducingmembrane of the present invention is to decrease the rate of release ofan underlying active ingredient. Accordingly, the polymer for formingthe rate-reducing membrane should be selected such that the activeingredient may not readily dissolve therein.

Polar substances are substances that have a dipole moment μ greater than0 Debye. As a general rule, polar substances dissolve well in otherpolar substances, such as water. Accordingly, polar substances can bebroadly categorized as “hydrophilic.” Polar substances typicallydissolve less readily in non-polar substances, which can be broadlycategorized as “hydrophobic.” The syllogism follows that a polar activeingredient will not readily dissolve in a hydrophobic polymer.Accordingly, a polymeric membrane that is hydrophobic may be employed toreduce the rate at which a polar active ingredient is released from animplantable device, such as a stent.

One method of defining the hydrophobicity of a polymer is by thesolubility parameter of the polymer. The solubility parameter isrepresented by Equation 1:δ=(ΔE/V)^(1/2)   (Equation 1)

where δ=solubility parameter ((cal/cm³)^(1/2))

-   -   ΔE=energy of vaporization (cal)    -   V=molar volume (cm³)        (“Polymer Handbook”, 2nd Ed., Brandrup J. and E H Immergut, ed.,        Wiley-Interscience, John Wiley & Sons, N.Y. (1975)). Because        polymers are typically non-volatile and thus cannot be vaporized        without decomposition, the solubility parameter is measured        indirectly. Briefly, solvents in which a polymer dissolves        without a change in heat or volume are identified. The        solubility parameter of the polymer is then defined to be the        same as the solubility parameters of the identified solvents.

As a general rule, the value of the solubility parameter δ is inverselyproportional to the degree of hydrophobicity of a polymer. Polymers thatare very hydrophobic may have a low solubility parameter value. Thisgeneral proposition is particularly applicable for polymers having aglass transition temperature below physiological temperature. A polymerthat is sufficiently hydrophobic for use in the rate-limiting membraneof the present invention can have a solubility parameter not more thanabout 11.5 (cal/cm³)^(1/2), more narrowly not more than about 10(cal/cm³)^(1/2), even more narrowly not more than 8.5 (cal/cm³)^(1/2).

Table 1 illustrates the solubility parameters of various polymers. TABLE1 Polymer Solubility Parameter (cal/cm³)^(1/2) polytetrafluoroethylene 6.2 polydimethylsiloxane 7.3-7.62 polyethylene 7.7-8.79polybutylmethacrylate 8.3-8.8  polypropylene 9.2-9.4  ethyl cellulose10.3 polyvinyl acetate 9.4-11.0

Another method of defining the hydrophobicity of a polymer is by theequilibrium moisture absorption factor. The equilibrium moistureabsorption factor is represented by Equation 2:MAF=(W _(w) /W _(p) +W _(w))×100   (Equation 2)

where MAF=equilibrium moisture absorption factor (%)

-   -   W_(w)=weight of water taken up by the polymer when immersed in        water or exposed to physiologic conditions    -   W_(p)=weight of the polymer

Generally, the less water absorbed by a polymer, and thus the lower theequilibrium moisture absorption factor, the better the polymer functionsas a diffusion barrier for a polar active ingredient. Upon absorption ofwater, a polymer can swell and the spaces between polymer chains canenlarge, allowing an active ingredient to diffuse more easily throughthe polymer. In addition, absorbed water provides an otherwise non-polarpolymer with polar water groups. These polar regions more readilydissolve a polar active ingredient via hydrogen bonding interactions,thereby allowing the active ingredient to diffuse through the otherwisenon-polar polymer more quickly. Thus, a polymer that is sufficientlyhydrophobic for use in the rate-limiting membrane of the presentinvention should have an equilibrium moisture absorption factor of lessthan about 5% by weight, more narrowly less than about 2%.Represeritative examples of such polymers includepolytetrafluoroethylene, perfluoro elastomers, fluoropolymers such aspolyvinylidene fluoride, ethylene-tetrafluoroethylene copolymer,fluoroethylene-alkyl vinyl ether copolymer, polyhexafluoropropylene, lowdensity linear polyethylenes having high molecular weights,ethylene-olefin copolymers, atactic polypropylene, polyisobutene,polybutylenes, polybutenes, styrene-ethylene-styrene block copolymers,styrene-butylene-styrene block copolymers,styrene-ethylene/butylene-styrene block copolymers,styrene-butadiene-styrene block copolymers, ethylene-anhydridecopolymers, ethylene vinyl acetate copolymers, polybutylmethacrylate,ethylene-acrylic acid copolymers of low acrylic acid content, ethylenemethacrylic acid copolymers of low methacrylic acid content, ethylenevinyl alcohol copolymers with an ethylene content greater than 48 molepercent, and cross-linked silicone elastomers.

In addition to having a solubility parameter not more than about 11.5(cal/cm³)^(1/2) and/or an equilibrium moisture absorption factor of lessthan about 5% by weight, the selected polymer should be biocompatible.The polymer should also be capable of being placed into solution at adesired concentration by a selected solvent, such as a non-polar solventso as to prevent dissolution of the polar active ingredient with thenon-polar solvent. Prevention of dissolution of the active ingredientduring the coating process of the rate-limiting layer significantlyreduces or eliminates the migration or leaching of the active componentout from the underlying reservoir layer or device. Accordingly, thequantity of active ingredient will not be reduced during the applicationof the rate-limiting layer.

Fluoropolymers are a suitable choice for the barrier layer composition.For example, the solubility parameter of polytetrafluoroethylene isabout 6.2 (cal/cm³)^(1/2), and the equilibrium moisture absorptionfactor is about 0.01%. Solution processing of fluoropolymers ispossible, particularly the low crystallinity varieties such as CYTOPavailable from Asahi Glass and TEFLON AF available from DuPont.Solutions of up to about 15% (wt/wt) are possible in perfluoro solvents,such as FC-75 (available from 3M under the brand name FLUORINERT), whichare non-polar, low boiling solvents. Such volatility allows the solventto be easily and quickly evaporated following the application of thepolymer-solvent solution to the medical device.

Another particularly suitable choice of polymer for the barrier layercomposition is styrene-ethylene/butylene-styrene block copolymer. Thesolubility parameter of this material lies in the range of from about7.7 (cal/cm³)^(1/2) to about 10.3 (cal/cm³)^(1/2), and the equilibriummoisture absorption factor is less than about 1%.Styrene-ethylene/butylene-styrene block copolymer, e.g., KratonG-series, can be dissolved in non-polar solvents such as, but notlimited to, toluene, xylene, and decalin.

Still other suitable choices of polymers for the rate-limiting membraneinclude, but are not limited to, ethylene-anhydride copolymers; ethylenevinyl acetate copolymers having, for example, a mol % of vinyl acetateof from about 9% to about 25%; and ethylene-acrylic acid copolymershaving, for example, a mol % of acrylic acid of from about 2% to about25%. The ethylene-anhydride copolymer available from Bynel adheres wellto EVAL and thus would function well as a topcoat over a reservoir layermade from EVAL. The copolymer can be dissolved in organic solvents, suchas dimethylsulfdxide and dimethylacetamide. Ethylene vinyl acetatepolymers can be dissolved in organic solvents, such as toluene andn-butyl acetate. Ethylene-acrylic acid copolymers can be dissolved inorganic solvents, such as methanol, isopropyl alcohol, anddimethylsulfoxide.

Yet another suitable choice of polymer for the rate-limiting membranecomposition is a cross-linked silicone elastomer. Such substances have asolubility parameter in the range of about 7.3 (cal/cm³)^(1/2) to about7.6 (cal/cm³)^(1/2), and an equilibrium moisture absorption factor ofless than about 0.5%. Loose silicone and silicone with very lowcross-linking are thought to cause an inflammatory biological response.However, it is believed that a thoroughly cross-linked siliconeelastomer, having low levels of leachable silicone polymer and oligomer,is an essentially non-inflammatory substance. Silicone elastomers, suchas Nusil MED-4750, MED-4755, or MED2-6640, having high tensilestrengths, for example between 1200 psi and 1500 psi, will likely havethe best durability during crimping, delivery, and expansion of a stentas well as good adhesion to a reservoir layer, e.g., EVAL or the surfaceof a medical device.

The embodiments of the composition for a rate-reducing membrane ordiffusion barrier layer are prepared by methods wherein all componentsare combined, then blended. More particularly, in accordance with oneembodiment, a predetermined amount of a polymeric compound is added to apredetermined amount of a compatible solvent. The selected solventshould be capable of placing the polymer into solution at theconcentration desired.

The polymeric compound can be added to the solvent at ambient pressureand under anhydrous atmosphere. If necessary, gentle heating andstirring and/or mixing can be employed to effect dissolution of thepolymer into the solvent, for example 12 hours in a water bath at about60° C. The polymer can comprise from about 0.1% to about 35%, morenarrowly from about 2% to about 20% by weight of the total weight of thecomposition, and the solvent can comprise from about 65% to about 99.9%,more narrowly from about 80% to about 98% by weight of the total weightof the composition. Selection of a specific weight ratio of the polymerand solvent is dependent on factors such as, but not limited to, thetype of polymer and solvent employed, the type of underlying reservoirlayer, and the method of application. Optionally, one of theaforementioned wetting fluids can also be added to the blend.

EXAMPLES OF THE DEVICE

The device or prosthesis used in conjunction with the above-describedcompositions may be any suitable medical substrate that can be implantedin a human or veterinary patient. Examples of such implantable devicesinclude self-expandable stents, balloon-expandable stents, stent-grafts,grafts, artificial heart valves, cerebrospinal fluid shunts, andpacemaker electrodes. The underlying structure of the device can bevirtually any design. The device can be made of a metallic material oran alloy such as, but not limited to, cobalt chromium alloy (ELGILOY),stainless steel (316L), high nitrogen stainless steel, e.g., BIODUR 108,cobalt chrome alloy L-605, “MP35N,” “MP20N,” ELASTINITE (Nitinol),tantalum, nickel-titanium alloy, platinum-iridium alloy, gold,magnesium, or combinations thereof. “MP35N” and “MP20N” are trade namesfor alloys of cobalt, nickel, chromium and molybdenum available fromstandard Press Steel Co., Jenkintown, Pa. “MP35N” consists of 35%cobalt, 35% nickel, 20% chromium, and 10% molybdenum. “MP20N” consistsof 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum. Devicesmade from bioabsorbable or biostable polymers could also be used withthe embodiments of the present invention.

It should be noted that the rate-reducing membrane or diffusion barrierlayer in accordance with various embodiments of the present inventioncan be used without the active ingredient-containing coating. In suchembodiments, the device may include cavities or micro-pores forcontaining the active ingredient such that the diffusion barrier layeris disposed over the cavities. The device can be formed by sintering thestent material from metallic particles, filaments, fibers or othermaterials. The device can be formed from a sintered wire that is coiledor otherwise formed into a device. The prosthesis can also be formedfrom a sintered cylindrical tube or sintered metal sheet which can belaser cut or chemical etched into an expandable stent structure.Formation of cavities via a sintering process is described in U.S. Pat.No. 5,843,172 to Yan. By way of another example, the surface of thedevice can be exposed to an etchant or a laser discharge to formcavities of selected dimensional specification.

Methods For Applying the Compositions to the Device

To form the optional primer layer and/or the activeingredient-containing coating on a surface of the device or prosthesis,the surface of the device should be clean and free from contaminantsthat may be introduced during manufacturing. However, the surface of theprosthesis requires no particular surface treatment to retain theapplied coating. Application of the composition can be by anyconventional method, such as by spraying the composition onto theprosthesis or by immersing the prosthesis in the composition. Operationssuch as wiping, centrifugation, blowing, or other web-clearing acts canalso be performed to achieve a more uniform coating. Briefly, wipingrefers to physical removal of excess coating from the surface of thestent; centrifugation refers to rapid rotation of the stent about anaxis of rotation; and blowing refers to application of air at a selectedpressure to the deposited coating. Any excess coating can also bevacuumed off the surface of the device. The addition of a wetting fluidleads to a consistent application of the composition which also causesthe coating to be uniformly deposited on the surface of the prosthesis.

With the use of the thermoplastic polymers for the primer, such asethylene vinyl alcohol copolymer, polycaprolactone,poly(lactide-co-glycolide), poly(hydroxybutyrate), etc., the depositedprimer composition should be exposed to a heat treatment at atemperature range greater than about the glass transition temperature(T_(g)) and less than about the melting temperature (T_(m)) of theselected polymer. Unexpected results have been discovered with treatmentof the composition under this temperature range, specifically strongadhesion or bonding of the coating to the metallic surface of a stent.The device should be exposed to the heat treatment for any suitableduration of time that would allow for the formation of the primercoating on the surface of the device as well as for the evaporation ofthe solvent or combination of solvent and wetting fluid. It isunderstood that essentially all of the solvent and the wetting fluidwill be removed from the composition, but traces or residues may remainblended with the polymer.

Table 2 lists the T_(g) and T_(m) for some of the polymers used in theembodiments of the present invention. T_(g) and T_(m) of polymers areattainable by one of ordinary skill in the art. The cited exemplarytemperature and time for exposure are provided by way of illustrationand are not meant to be limiting. TABLE 2 Exemplary Exemplary Durationof Temperature Time For Polymer T_(g) (° C.) T_(m) (° C.) (° C.) HeatingEVAL 55 165 140 4 hours polycaprolactone −60 60 50 2 hours ethylenevinyl 36 63 45 2 hours acetate (e.g., 33% vinyl acetate content)Polyvinyl 75-85* 200-220* 165 2 hours alcohol*Exact temperature depends on the degree of hydrolysis which is alsoknown as the amount of residual acetate.

With the use of one of the aforementioned thermoset primer polymers, theuse of initiators may be required. By way of example, epoxy systemsconsisting of diglycidyl ether of bisphenol A resins can be cured withamine curatives, thermoset polyurethane prepolymers can cured withpolyols, polyamines, or water (moisture), and acrylated urethane can becured with UV light. If baked, the temperature can be above the T_(g) ofthe selected polymer.

With the use of the inorganic primer polymers, such as silanes,titanates, and zirconates, the solvent is allowed to evaporate.

The composition containing the active ingredient can be applied to adesignated region of the primer coating or the surface of the device.The solvent(s) or the combination of solvent(s) and the wetting fluid isremoved from the composition by allowing the solvent(s) or combinationof the solvent(s) and the wetting fluid to evaporate. The evaporationcan be induced by heating the device at a predetermined temperature fora predetermined period of time. For example, the device can be heated ata temperature of about 60° C. for about 12 hours to about 24 hours. Theheating can be conducted in an anhydrous atmosphere and at ambientpressure and should not exceed the temperature which would adverselyaffect the active ingredient. The heating can, alternatively, beconducted under a vacuum condition. It is understood that essentiallyall of the solvent and the wetting fluid will be removed from thecomposition, but traces or residues may remain blended with the polymer.

The diffusion barrier layer can be formed on a designated region of theactive ingredient-containing coating subsequent to the evaporation ofthe solvent(s) or solvent(s)/wetting fluid and the drying of the polymerfor the active ingredient-containing coating. Alternatively, inembodiments in which a polymeric reservoir coating is not employed, therate-reducing membrane may be formed directly over active-ingredientcontaining cavities within the surface of the prosthesis. The diffusionbarrier layer can be applied by spraying the composition onto the deviceor immersing the device in the composition, then drying the polymer. Theabove-described processes can be similarly repeated for the formation ofthe diffusion barrier layer.

Coating

Some of the various embodiments of the present invention are illustratedby FIGS. 2A, 2B, and 2C. The Figures have not been drawn to scale, andthe thickness of the various layers have been over or under emphasizedfor illustrative purposes.

Referring to FIG. 2A, a body of a medical substrate 20, such as a stent,is illustrated having a surface 22. Medical substrate 20 includescavities or micro-pores 24 formed in the body for releasably containingan active ingredient, as illustrated by dotted region 26. A diffusionbarrier layer or rate-reducing membrane 28 is disposed on surface 22 ofmedical substrate 20, covering cavities 24. Diffusion barrier layer 28functions to reduce the rate of release of an active ingredient frommedical substrate 20.

Referring to FIG. 2B, medical substrate 20 is illustrated having aprimer layer 30 formed on surface 22. An active ingredient-containing orreservoir coating 32 is deposited on primer layer 30. Primer layer 30serves as an intermediary layer for increasing the adhesion betweenreservoir coating 32 and surface 22. Increasing the amount of activeingredient admixed within the polymer diminishes the adhesiveness ofreservoir layer 32 to surface 22. Accordingly, using an activeingredient-free polymer as an intermediary primer layer 30 allows for ahigher active ingredient content for reservoir layer 32. Diffusionbarrier 28 is formed over at least a selected portion of reservoir layer32. One of ordinary skill in the art can appreciate that diffusionbarrier layer 28 can be deposited only on selected areas of reservoirlayer 32 so as to provide a variety of selected release parameters. Suchselected patterns may become particularly useful if a combination ofactive ingredients are used, each of which requires a different releaseparameter.

FIG. 2C illustrates medical substrate 20 having a first reservoir layer32A disposed on a selected portion of surface 22 of medical substrate20. First reservoir layer 32A contains a first active ingredient, e.g.,actinomycin D. A second reservoir layer 32B can also be disposed onsurface 22. Second reservoir layer 32B contains a second activeingredient, e.g., taxol. First and second reservoir layers 32A and 32Bare covered by first and second diffusion barrier layers 28A and 28B,respectively. In accordance with one embodiment, the polymeric materialfrom which diffusion barrier layer 28A is made can be different than thematerial from which diffusion barrier layer 28B is made. Accordingly, awide array of release parameters can be obtained for any selectedcombination of active ingredients.

Diffusion barrier layer 28 can have any suitable thickness, as thethickness of diffusion barrier layer 28 is dependent on parameters suchas, but not limited to, the desired rate of release and the procedurefor which the stent will be used. Diffusion barrier layer 28 can have athickness of about 0.1 to about 10 microns, more narrowly from about0.25 to about 5 microns.

By way of example, and not limitation, the impregnated reservoir layer32 can have a thickness of about 0.5 microns to about 1.5 microns. Theparticular thickness of reservoir layer 32 is based on the type ofprocedure for which medical substrate 20 is employed and the amount ofthe active ingredient to be delivered. The amount of the activeingredient to be included on the prosthesis can be further increased byapplying a plurality of reservoir layers 32 on top of one another. Theoptional primer layer 30 can have any suitable thickness, examples ofwhich can be in the range of about 0.1 to about 10 microns, morenarrowly about 0.1 to about 2 microns.

Method of Use

In accordance with the above-described method, the active ingredient canbe applied to a device, e.g., a stent, retained on the device duringdelivery and released at a desired control rate and for a predeterminedduration of time at the site of implantation. A stent having theabove-described coating layers is useful for a variety of medicalprocedures, including, by way of example, treatment of obstructionscaused by tumors in bile ducts, esophagus, trachea/bronchi and otherbiological passageways. A stent having the above-described coatinglayers is particularly useful for treating occluded regions of bloodvessels caused by abnormal or inappropriate migration and proliferationof smooth muscle cells, thrombosis, and restenosis. Stents may be placedin a wide array of blood vessels, both arteries and veins.Representative examples of sites include the iliac, renal, and coronaryarteries.

Briefly, an angiogram is first performed to determine the appropriatepositioning for stent therapy. Angiography is typically accomplished byinjecting a radiopaque contrasting agent through a catheter insertedinto an artery or vein as an x-ray is taken. A guidewire is thenadvanced through the lesion or proposed site of treatment. Over theguidewire is passed a delivery catheter, which allows a stent in itscollapsed configuration to be inserted into the passageway. The deliverycatheter is inserted either percutaneously, or by surgery, into thefemoral artery, brachial artery, femoral vein, or brachial vein, andadvanced into the appropriate blood vessel by steering the catheterthrough the vascular system under fluoroscopic guidance. A stent havingthe above-described coating layers may then be expanded at the desiredarea of treatment. A post insertion angiogram may also be utilized toconfirm appropriate positioning.

EXAMPLES

The embodiments of the invention will be illustrated by the followingset forth prophetic examples which are being given by way ofillustration only and not by way of limitation. All parameters and dataare not to be construed to unduly limit the scope of the embodiments ofthe invention.

Example 1

A 13 mm, 316L stainless steel TETRA stent is primer coated by sprayingwith a 2% (w/w) solution of poly(ethylene-co-vinyl alcohol) (44 mole %ethylene) in dimethylacetamide. The solvent is removed by baking at 140°C. for 1 hour. A solution of 2% (w/w) EVAL and 0.25% (w/w) actinomycin Din dimethylacetamide is spray coated onto the stent to a thickness thatgives 25 μg of actinomycin D on the stent. The stent is then baked at50° C. for two hours. A hydrophobic release rate limiting membrane isformed by spraying the stent with a 2% (w/w) solution ofpolybutylmethacrylate in a ⅓ (w/w) mixture of ethyl acetate andcyclohexanone. A second two hour bake at 50° C. is performed to removethe solvent.

Example 2

A 13 mm, 316L stainless steel TETRA stent is primer coated by sprayingwith a 2% (w/w) solution of poly(ethylene-co-vinyl alcohol) (44 mole %ethylene) in dimethylacetamide. The solvent is removed by baking at 140°C. for 1 hour. A solution of 2% (w/w) EVAL and 0.5% (w/w) paclitaxel indimethylacetamide is spray coated onto the stent to a thickness thatgives 50 μg of paclitaxel on the stent. The stent is then baked at 50°C. for two hours. A hydrophobic release rate limiting membrane is formedby spraying on a 2% (w/w) solution of poly(ethylene-co-vinylacetate) (25mole % acetate content) in a 1/1 (w/w) solution of toluene and n-butylacetate. Another two hour bake at 50° C. is performed to remove thesolvent.

Example 3

A 13 mm, 316L stainless steel TETRA stent is primer coated by sprayingwith a 2% (w/w) solution of poly(ethylene-co-vinyl alcohol) (44 mole %ethylene) in dimethylacetamide. The solvent is removed by baking at 140°C. for 1 hour. A solution of 2% (w/w) EVAL and 0.67% (w/w) clobetasolpropionate in dimethylacetamide is spray coated onto the stent to athickness that gives 150 μg of clobetasol propionate on the stent. Thestent is then baked at 50° C. for two hours. A hydrophobic release ratelimiting membrane is formed by coating on a 5% (w/w) solution of NusilMED3-6605 silicone dispersion in a 1/1 (w/w) of trichloroethylene andcyclohexane. This process is accomplished by placing the stent on asection of 0.070 inch OD stainless steel tubing. The coating is thenapplied to the stent via syringe. With the stent covered with fluid, itis pushed along the length of the tube with a short section of TEFLONtubing, while simultaneously rotating the stainless steel tube. Thecoating is left to air cure at ambient temperature for 18 hours.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. For example, while much of the abovediscussion focuses on the reduction of the rate of diffusion of a polaractive ingredient, one of ordinary skill in the art will understand thatthe diffusion barriers described are also applicable for use withnon-polar active ingredients. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

1. A method of forming a coating for a medical device carrying an agent,comprising: applying a first composition including a polymer to at leasta portion of a medical device to form a first coating, said polymerhaving a solubility parameter not greater than approximately 11.5(cal/cm³)^(1/2), and wherein said first coating reduces the rate ofrelease of said agent from said medical device.
 2. A coating for amedical device produced in accordance with the method of claim
 1. 3. Themethod of claim 1, wherein said medical device is a balloon expandablestent, a self-expandable stent, a stent-graft, or a graft.
 4. The methodof claim 1, wherein said medical device is a metallic stent havingcavities containing said agent for the release of said agent subsequentto the implantation of said stent in a mammalian lumen, and wherein saidfirst coating is formed on the surface of said metallic stent andcovering said cavities.
 5. The method of claim 1, wherein said agent isa polar substance.
 6. The method of claim 1, wherein said first coatingis hydrophobic, and wherein said agent is a polar substance.
 7. Themethod of claim 1, wherein said first composition additionally includesa solvent capable of dissolving said polymer, said method additionallycomprising evaporating said solvent to form said first coating.
 8. Themethod of claim 7, wherein said solvent is non-polar and capable ofdissolving said polymer.
 9. The method of claim 7, wherein said solventis non-polar and capable of dissolving the polymer but not the agent.10. The method of claim 1, wherein said agent is selected from a groupof actinomycin D, docetaxel, paclitaxel, and rapamycin.
 11. The methodof claim 1, wherein said polymer has an equilibrium water absorptionfactor of less than about 5% by weight under physiologic conditions. 12.The method of claim 1, additionally comprising prior to said applying afirst composition: (a) applying a second composition including a solventand a polymer to the surface of said medical device; (b) evaporatingsaid solvent of said second composition to form a second coating on thesurface of said medical device; (c) applying a third compositionincluding a solvent, a polymer, and an agent on said second coating; and(d) evaporating said solvent of said third composition to form a thirdcoating containing said agent in said second coating, wherein said firstcoating reduces the rate of release of said agent.
 13. The method ofclaim 1, additionally comprising prior to said applying a firstcomposition: (a) applying a second composition including a solvent, apolymer, and an agent to the surface of said medical device; and (b)evaporating said solvent of said second composition to form a secondcoating containing said agent on the surface of said medical device,wherein said first coating reduces the rate of release of said agent.14. The method of claim 1, wherein said polymer has a solubilityparameter not greater than approximately 10 (cal/cm³)^(1/2).
 15. Themethod of claim 1, wherein said polymer has a solubility parameter notgreater than approximately 8.5 (cal/cm³)^(1/2).
 16. A composition forforming a coating on a medical device comprising: (a) a solvent; and (b)a hydrophobic polymer dissolved in said solvent, wherein said polymerhas an equilibrium water absorption factor of less than about 5% byweight by weight under physiological conditions.
 17. The composition ofclaim 16, wherein said solvent is non-polar and capable of dissolvingsaid polymer.
 18. A polymeric coating produced by the evaporation ofsaid solvent from said composition of claim
 16. 19. The composition ofclaim 16, wherein said polymer is selected from a group ofpolytetrafluoroethylene, perfluoro elastomers, fluoropolymers,ethylene-tetrafluoroethylene copolymer, fluoroethylene-alkyl vinyl ethercopolymer, polyhexafluoropropylene, low density linear polyethyleneshaving high molecular weights, ethylene-olefin copolymers, atacticpolypropylene, polyisobutene, polybutylenes, styrene-ethylene-styreneblock copolymers, styrene-butylene-styrene block copolymers,styrene-ethylene/butlene-styrene block copolymers,styrene-butadiene-styrene block copolymers, ethylene-anhydridecopolymers, ethylene vinyl acetate copolymers, ethylene-acrylic acidcopolymers, ethylene methacrylic acid copolymers, polyurethanes with apolydimethylsiloxane soft segment, ethylene vinyl alcohol copolymerswith an ethylene content greater than 48 mole percent, and cross-linkedsilicone elastomers.
 20. The composition of claim 16, wherein saidmedical device is a radially expandable stent.
 21. The composition ofclaim 16, wherein said coating formed from said composition is used forreducing the rate of release of a therapeutic agent from said medicaldevice.
 22. The composition of claim 16, wherein said polymer has asolubility parameter not greater than approximately 11.5(cal/cm³)^(1/2).
 23. The composition of claim 16, wherein said polymerhas a solubility parameter not greater than approximately 8.5(cal/cm³)^(1/2).
 24. An implantable medical device for carrying atherapeutic agent, comprising: a first coating including a polymericmaterial, said polymeric material having a solubility parameter notgreater that approximately 11.5 (cal/cm³)^(1/2), wherein said firstcoating reduces the rate of release of said agent.
 25. The device ofclaim 24, wherein said polymeric material is hydrophobic and saidtherapeutic agent is polar.
 26. The device of claim 24, wherein saidpolymeric material is non-polar and said therapeutic agent is polar. 27.The device of claim 24, additionally comprising: (a) a second polymericcoating formed on the surface of said medical device; and (b) a thirdpolymeric coating including an agent formed on said second polymericcoating and beneath said first polymeric coating, wherein said firstpolymeric coating reduces the rate of release of said agent.
 28. Thedevice of claim 24, additionally comprising: (a) a second polymericcoating including an agent formed on the surface of said medical deviceand beneath said first polymeric coating, wherein said first polymericcoating reduces the rate of release of said agent.
 29. The device ofclaim 24, wherein said polymeric material is selected from a group ofpolytetrafluoroethylene, perfluoro elastomers, fluoropolymers,ethylene-tetrafluoroethylene copolymer, fluoroethylene-alkyl vinyl ethercopolymer, polyhexafluoropropylene, low density linear polyethyleneshaving high molecular weights, ethylene-olefin copolymers, atacticpolypropylene, polyisobutene, polybutylenes, styrene-ethylene-styreneblock copolymers, styrene-butylene-styrene block copolymers,styrene-ethylene/butlene-styrene block copolymers,styrene-butadiene-styrene block copolymers, ethylene-anhydridecopolymers, ethylene vinyl acetate copolymers, ethylene-acrylic acidcopolymers, ethylene methacrylic acid copolymers, polyurethanes with apolydimethylsiloxane soft segment, ethylene vinyl alcohol copolymerswith an ethylene content greater than 48 mole percent, and cross-linkedsilicone elastomers.
 30. The device of claim 24, wherein saidimplantable medical device is a radially expandable metallic stent. 31.The device of claim 30, wherein said metallic stent includes cavitiescontaining said agent for the release of said agent subsequent to theimplantation of said stent in a mammalian lumen, and wherein said firstpolymeric coating is formed on the surface of said metallic stent andcovering said cavities.
 32. The device of claim 24, wherein saidpolymeric material has an equilibrium water absorption factor of lessthan about 5% by weight under physiologic conditions.